1. Field of the Invention
The present invention relates to a method for preparing N.sup.2 -arylsulfonyl-L-arginineamides which are useful as active ingredients of medicaments such as anti-thrombotic agents.
2. Related Art
The Japanese Patent Publication (KOKOKU) No. (Sho) 61-48829/1986 discloses, as Compound No. 6 in Table 1, (2R,4R)-4-methyl-1-N.sup.2 -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine -carboxylic acid. As taught by the publication, this compound has highly specific inhibitory activity against thrombin that exists in a mammalian body, and is useful as an agent for therapeutic and preventive treatment of thrombosis, and as a platelet aggregation inhibitor. Monohydrate of this compound has been used as a selective anti-thrombotic agent for the treatment of chronic arterial occulsive diseases, cerebral thrombosis or other.
As a method for preparing the N.sup.2 -arylsulfonyl-L-arginineamides such as mentioned above, the method set out in the scheme below was known so far, as disclosed on pages 2 and 3 of the Japanese Patent Publication (KOKOKU) No. (Hei) 1-35000/1989 and on page 3 of the Japanese Patent Publication (KOKOKU) No. (Hei) 2-31055/1990. In the scheme, Ar represents 1,2,3,4-tetrahydro-8-quinolyl group whose 3-position is substituted with methyl group or ethyl group; Q represents 8-quinolyl group whose 3-position is substituted with methyl group or ethyl group; R.sup.1 represents a hydrogen atom or a C.sub.1-5 alkyl group; X represents a halogen atom; R.sup.2 represents a hydrogen atom, a C.sub.1-10 alkyl group, or a C.sub.7-15 aralkyl group; at least one of R' and R" represents a protective group of the guanidino group; and R"' represents a protective group of the .alpha.-amino group. ##STR1##
This method comprises the steps of condensing a piperidine-2-carboxylic acid derivative (Compound (IV) in the scheme) with an arginine derivative whose guanidino group and amino group on the .alpha.-carbon atom are appropriately protected (Compound (III) in the scheme); removing the protective group of the amino group on the .alpha.-carbon of the condensate obtained (Compound (V) in the scheme) and then allowing the resulting amino group react with a quinolinesulfonyl halide (Compound (VII) in the scheme); followed by removing the substituent on the guanidino group such as nitro group, and then reducing the quinolyl group and deblocking the carboxyl group to obtain the desired compound (Compound (I) in the scheme).
The Japanese Patent Publication (KOKOKU) No. (Sho) 61-48829/1986 discloses, as Example 2 on page 7, a specific process for preparing (2R,4R)-4-methyl-1-N.sup.2 -(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl!-2-piperidine -carboxylic acid according to the aforementioned method. The publication discloses that the ethyl ester of (2R,4R)-1-N.sup.G -nitro-N.sup.2 -(3-methyl-8-quinolinesulfonyl)-L-arginyl!-4-methyl-2-piperidine-carboxyli c acid was prepared in the three-step process by using N.sup.G -nitro-N.sup.2 -(tert-butoxycarbonyl)-L-arginine as a starting material, and the yield of step (A) was 74.5%.
The Japanese Patent Publication (KOKOKU) No. (Hei) 1-35000/1989 discloses the reaction scheme on pages 4 and 5 that relates to a process comprising the steps of condensing unprotected L-arginine (Compound (II) in the scheme) with an approximately equimolar amount of a quinolinesulfonyl halide (Compound (VII) in the scheme) to obtain N.sup.2 -quinolinesulfonyl-L-arginine (Compound (IX) in the scheme), and then allowing the resulting product react with the piperidine-2-carboxylic acid derivative (Compound (IV) in the scheme), followed by reducing the quinolyl group and deblocking the carboxyl group to obtain the desired compound, which will be shown in the scheme below. However, this method is not specifically demonstrated by any working example given in the publication, and moreover, it is impossible to obtain the desired compound with high selectivity, because the publication fails to teach any specific means to control the sulfonylation of the unprotected guanidino group which must be expected as an inevitable side reaction. Therefore, this method is of no significance to industrial applications. In addition, the publication neither teaches nor suggests a process of reacting an arginine having a protected guanidino group, e.g., Compound (III) shown in the scheme, with a quinolinesulfonyl halide according to the aforementioned method. ##STR2##
Therefore, an object of the present invention is to provide a method that enables efficient preparation of N.sup.2 -arylsulfonyl-L-arginineamides on an industrial scale. Another object of the present invention is to provide a synthetic intermediate compound which is useful for efficient preparation of N.sup.2 -arylsulfonyl-L-arginineamides.